Inverse electron-demand Diels-Alder reactions oxazole

In addition to the [4 + 2] cycloadditions of oxazoles (Section 1) and substituted 1,2,4,5-tetrazines (Section 14), the Diels-Alder cycloadditions of substituted 1,2,4-triazines constitute one of the most thoroughly investigated heteroaromatic azadiene systems capable of 4tt diene participation.3,89 In contrast to the oxazole or sym-tetrazine series, two potential and observed modes of cycloaddition are open to 1,2,4-triazines cycloaddition across C-3/C-6 or C-5/N-2 of the 1,2,4-triazine nucleus, and the former is subject to 1,2,4-triazine substituent control of the observed regioselectivity.90 The complementary addition of electron-withdrawing substituents to the 1,2,4-triazine nucleus generally increases its rate of participation in inverse electron demand Diels-Alder reactions, influences the mode of [4 + 2] cycloaddition (C-3/C-6 versus C-5/N-2 cycloaddition), and controls the observed regioselectivity. In addition, the reactivity of the electron-rich dienophile as well as the reaction conditions, polar versus nonpolar solvent, have a pronounced effect on the observed course of the [4 -I- 2] cycloadditions.89... 

Diels-Alder reaction between oxazole and alkenes and subsequent rearomatization of the cycloadducts provides access to substituted p3nidines and other natural products that can be difficult to obtain via other synthetic means. Oxazole can participate in both inverse electron-demand Diels-Alder (lEDDA) reactions as an electron-poor diene and in normal electron-demand Diels-Alder reactions (NEDDA) as an electron-rich diene. NEDDA reactions often involve harsh conditions and high temperatures, whereas lEDDA reactions require substitution with electron-withdrawing groups onto the oxazole moiety or Brpnsted/Lewis acid catalysis to promote reactivity. 

Few reactions of the parent oxazole with the usual alkenic and alkynic dienophiles have been reported. Most oxazoles which yield Diels-Alder adducts contain electron-releasing substituents, the order of reactivity being alkoxy> alkyl 4-phenyl > acetyl > ethoxycarbonyl. This sequence suggests that the oxazole functions as the electron-rich component and that the reaction is governed by interaction of the highest occupied molecular orbital of the oxazole and the lowest unoccupied orbital of the dienophile. Cycloadditions with inverse electron demand of electron-deficient oxazoles with electron-rich dienophiles can be envisaged. 

Five-membered heteroaromatic systems that possess an electron-deficient azadiene substructure, e.g., oxazoles and thiazoles, are suitable for participation in Diels-Alder reactions with inverse electron-demand [49JA3062 59JA4342 62AG(E)329]. The introduction of strongly electron-donating substituents in many cases is sufficient to overcome the electron-deficient nature of the azadiene moiety and permits normal HOMO diene/ LUMO dienophile controlled Diels-Alder reactions (87MI6). 

Despite the early recognition that heterocyclic azadiene systems are typically electron-deficient,1 little effort has been devoted to the exploration of the potential participation of electron-deficient oxazoles in inverse electron demand (LUMOdiene controlled) Diels-Alder reactions with electron-rich or simple olefinic dienophiles. One study has demonstrated the potential of such investigations (Table 10-1, entry 26).34 Breslow and coworkers have adapted the oxazole olefin Diels-Alder reaction for the preparation of a tetrahydroquinoline-based analog of pyridoxamine with the stereochemically defined placement of a catalytic group [Eq. (2)].37b... 

The ring enlargement of pyrroles providing 3-chloropyridines has already been described (see p 93). Oxazoles react as masked 2-azadienes with alkenes yielding pyridine derivatives of various types (see p 131). With enamines and ynamines, diazines and triazines undergo Diels-Alder reactions with inverse electron demand (see p 441). This leads to pyridines (e.g. 201) by the enamine cycloaddition of the 1,2,4-triazine, as shown below ... 

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